IGFBP-4 fragments as markers of cardiovascular mortality in type 1 diabetes patients with and without nephropathy

CONTEXT: Type 1 diabetes (T1D) is characterized by an increased risk of macro-vascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of insulin-like growth factor binding protein-4 (NT-IGFBP-4/CT-IGFBP-4) have been suggested as cardiac biomarkers.

OBJECTIVE: To investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients.

DESIGN AND PATIENTS: We prospectively followed 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (0.2-12.9) years.

MAIN OUTCOME MEASURES: Levels of IGF-I, IGF-II, IGFBP-1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline.

RESULTS: During follow-up, 15 patients with normoalbuminuria and 71 patients with nephropathy died. Of these deaths, eight and 45 were due to fatal cardiovascular events, respectively. Using receiver operating characteristic curve analyses, patients were divided into subgroups using cut-off values of 261 μ g/L NT-IGFBP-4, 81 μ g/L CT-IGFBP-4 or 10 mIU/L PAPP-A. All-cause mortality was significantly higher in patients with NT-IGFBP-4 levels (55% vs. 16%, p<0.001) and CT-IGFBP-4 levels (44% vs. 15%, p<0.001) above vs. below cut-offs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40% vs. 7.8%, p<0.001) and high CT-IGFBP-4 levels (30% vs. 7.4%, p<0.001). After adjustments for nephropathy and traditional cardiovascular risk factors, high NT- and CT-IGFBP-4 levels remained prognostic of cardiovascular mortality with hazard ratios (HR) (95% confidence interval) of 5.81 (2.62;12.86) (p<0.001) and 2.58 (1.10;6.10) (p=0.030), respectively. After adjustments, PAPP-A was not associated with overall or cardiovascular death. All IGF protein levels were higher in patients with diabetic nephropathy (p<0.001), but no variables associated with mortality.

CONCLUSION: High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy.